Uses of indolinone compounds

ABSTRACT

Methods and compositions for treating acute myeloid leukemia and diffuse large B cell lymphoma using combinations of venetoclax and indolinone derivatives are provided.

INCORPORATION BY REFERENCE TO RELATED APPLICATIONS

Any and all priority claims identified in the Application Data Sheet, orany correction thereto, are hereby incorporated by reference under 37CFR 1.57. This application is a continuation of U.S. application Ser.No. 16/114,076, filed Aug. 27, 2018, which is a continuation of U.S.application Ser. No. 15/660,566, filed Jul. 26, 2017, now U.S. Pat. No.10,159,660, which claims the benefit of U.S. Provisional Application No.62/368,707, filed Jul. 29, 2016, U.S. Provisional Application No.62/417,572, filed Nov. 4, 2016, U.S. Provisional Application No.62/422,504, filed Nov. 15, 2016, U.S. Provisional Application No.62/426,107, filed Nov. 23, 2016, U.S. Provisional Application No.62/503,238, filed May 8, 2017, and U.S. Provisional Application No.62/534,067, filed Jul. 18, 2017. Each of the aforementioned applicationsis incorporated by reference herein in its entirety, and each is herebyexpressly made a part of this specification.

FIELD

Methods and compositions for treating acute myeloid leukemia and diffuselarge B cell lymphoma using indolinone derivatives are provided.

BACKGROUND

The EWS-FLI transcription factor present in vast variety of Ewing'ssarcoma family of tumors (ESFT) was characterized over ten years ago.Progress in the treatment of Ewing's sarcoma the second most common bonetumor in children and adolescents, has improved survival for patientswith localized tumors. However, patients with metastases still farebadly and the therapy carries short and long-term toxicities. The Ewingsarcoma family of tumors (ESFT) is characterized by a chromosomaltranslocation that generates EWS-FLI1, on oncogenic fusion transcriptionfactor whose continued expression is believed to be critical for ESFTcell survival (Balamuth, N J, Womer, R B., Lancet Oncology 11, 184-192(2010)). ETS transcription factors, such as FLI1 and SPIB, arerecurrently deregulated in human lymphomas (Bonetti et al, Blood 2013;Lenz et al, PNAS 2008). The small molecule YK-4-279 inhibits binding ofEWS1-FLI1 fusion protein to RHA resulting in growth arrest and apoptosisin Ewing sarcoma cells (Erkizan et al, Nat Med 2009) and it waspreviously showed that YK-4-279 has in vitro anti-lymphoma activity(Chung et al, AACR 2015).

In vitro and in vivo studies have demonstrated that the inhibition ofthe binding of the oncoprotein, EWS-FLI1, to RNA Helicase A (RHA) leadsto a decrease in proliferation of ESFT cell lines and a decrease oftumor volume. EWS-FLI1 lacks enzymatic activity, however, theprotein-protein interaction between RNA helicase A (RHA) andEWS-FLI1-modulates oncogenesis, and is therefore required for themaintenance of the tumor growth (Hyariye N Erkizan et al. NatureMedicine 15(7) 750-756 (2009)). The paradigm of disrupting key proteininteractions may have utility in treatment of diseases includingsarcomas with similar translocations, and leukemias with MLLtranslocations ((Helman L J, Meltzer P. Mechanisms of sarcomadevelopment. Nat Rev Cancer 2003; 3(9):685-94); and Pui C H, et al., NEngl J Med 2004; 350(15):1535-48). Moreover, disordered proteins may beexcellent therapeutic targets based on their intrinsic biochemicalproperties (Cheng Y, LeGall T, Oldfield C J, et al., Trends Biotechnol2006; 24(10):435-42).

SUMMARY

Despite years of in vitro and xenograft studies with antisense and siRNAdirected towards EWS-FLI1, none of these is heretofore practical as ahuman therapy based on inadequate delivery and stability. Accordingly,there is a need for improved therapies to treat disorders such as ESFTs.

FLI-1 is a member of the ETS family transcription factors which arenormally active in the developing embryo, but not after birth. There are29 members of this family of transcription factors, four of which,FLI-1, ETV1, ETV4 and ERG, have been associated with a wide range ofcancers.

Therapeutic compounds targeting the inhibition of the binding ofoncogenic fusion proteins of FLIT, ETV1, ETV4 or ERG or thetranscription factors themselves will have utility in treatment ofcancers including the Ewing's sarcoma family of tumors, pancreaticcancer, prostate cancer, glioblastoma, non-small cell lung cancer, andseveral other cancers. The preferred embodiments fulfill these needs,and provide other advantages as well.

Some embodiments disclosed herein relate to a compound of Formula (I)including forms such as stereoisomers, free forms, pharmaceuticallyacceptable salts or esters thereof, solvates, or combinations of suchforms, wherein A, D, R₁, R₂, R₃, R₄, R₅, R₆, and R₁₂ are as definedherein.

Some embodiments disclosed herein relate to methods for treating cancerin a mammal, comprising administering to the mammal an effective amountof one or more compounds of Formula (I) including forms such asstereoisomers, free forms, or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition that includes one or morecompounds of Formula (I) including forms such as stereoisomers, freeforms, or a pharmaceutically acceptable salt thereof,. Other embodimentsdescribed herein relate to using one or more compounds of Formula (I)including forms such as stereoisomers, free forms, or a pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament fortreatment of cancer.

Still other embodiments described herein relate to a compound of Formula(I) including forms such as stereoisomers, free forms, or apharmaceutically acceptable salt thereof, for treatment of cancerwherein the cancer is selected from the group consisting of Ewing'ssarcoma, glioblastoma, acute myeloid leukemia, breast cancer, head &neck cancer, melanoma, non-small cell lung cancer, ovarian cancer,prostate cancer, and uterine cancer. These and other embodiments aredescribed in greater detail below.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram illustrating that TK216 (also referred to herein asTK-216, which is4,7-Dichloro-3-(2-(4-cyclopropylphenyl)-2-oxoethyl)-3-hydroxyindolin-2-one)is active in oncogenesis and inhibits aptosis.

FIG. 2 shows TK216 treatment inhibited EWS-FLI1 protein interactions,leading to a decrease in transcription and proliferation.

FIG. 3 shows TK216 reduced transcriptional activity in COST cellsco-transfected with EWS-FLI1 and NROB1 reporter-luciferase plasmidswhich contain EWS-FLI1 DNA-binding sites.

FIG. 4 shows treatment with TK216 resulted in a dose-dependentinhibition of proliferation in Ewing Sarcoma A4573 cell line.

FIG. 5 shows TK216 displayed anti-proliferative activity in AML celllines.

FIG. 6 shows TK216 displayed anti-proliferative activity in DLBCL celllines.

FIG. 7 and FIG. 8 show TK216 induced apoptosis in DLBCL cell lines, withthe amount of cleaved-Caspase 3 normalized to b-actin and presented asfold over control.

FIG. 9 shows TK216 displayed synergy when combined with BCL-2 (ABT199)inhibitors, wherein CalcuSyn software was used to determine theCombination Index (CI) using the Chou/Talalay equation.

FIG. 10 show TK216 displayed synergy when combined with BTK (ACP196)inhibitors, wherein CalcuSyn software was used to determine theCombination Index (CI) using the Chou/Talalay equation.

FIG. 11 shows TK216 displayed anti-tumor activity in a TMD8 xenograftmodel.

FIG. 12 shows treatment with TK216 results in tumor growth inhibition ofthe TMD-8 xenograft model when compared to vehicle control following 13days of treatment.

FIG. 13 is a dose-effect curve for TK216 in combination with venetoclaxin the TMD8 cell line, wherein the top curve (×) was for the combinationtherapy, the middle curve (⊚) was for TK216, and the bottom curve (+)was for venetoclax.

FIG. 14 is a dose-effect curve for TK216 in combination with venetoclaxin the U2932 cell line, wherein the top curve (×) was for thecombination therapy, the middle curve (⊚) was for TK216, and the bottomcurve (+) was for venetoclax.

FIG. 15 is a dose-effect curve for TK216 in combination with venetoclaxin the HLB1 cell line, wherein the top curve (×) was for the combinationtherapy, the middle curve (⊚) was for TK216, and the bottom curve (+)was for venetoclax.

FIG. 16 shows the results of dose-effect testing conducted in DLBLC celllines (TMD8, HBL1, U2932), indicating a synergistic effect across doses.

FIG. 17 shows the distribution of IC50 values for TK-216 in lymphomacell lines by individual histologies. Y-axis: IC50 values. In eachbox-plot, the line in the middle of the box represents the median andthe box extends from the 25th to the 75th percentile (interquartilerange, IQ); the whiskers extend to the upper and lower adjacent values(i.e., ±1.5 IQ).

FIGS. 18A and 18B show apoptosis and cell cycle distribution of TK-216in DLBCL cell lines. FIG. 18A) Induction of apoptosis in DLBCL celllines exposed to TK-216 (500 nM) for 24, 48 or 72 hrs. In the figuresare shown four representative (two ABC and two GCB) results. FIG. 18B)Cell cycle distribution in DLBCL cell lines treated with 500 nM ofTK-216 for 24, 48 or 72 hrs. In the figure, two representative (one ABCand one GCB) results are shown. DMSO treatment was used as a control.

FIG. 19 shows the effects of TK-216 in a xenograft model of ABC-DLBCL.NOD-Scid mice subcutaneously inoculated with TMD8 cells (15×10⁶) weresplit in two groups respectively treated with TK-216 (100 mg/kg, BID,po, n=9) and control vehicle (n=10). In each box-plot, the line in themiddle of the box represents the median and the box extends from the25th to the 75th percentile (interquartile range, IQ); the whiskersextend to the upper and lower adjacent values (i.e., ±1.5 IQ).

FIG. 20 shows TK216 combinations in DLBCL cell lines: box-plots of theCI values obtained in individual cell lines. Y-axis: CI values. In eachbox-plot, the line in the middle of the box represents the median andthe box extends from the 25th to the 75th percentile (interquartilerange, IQ); the whiskers extend to the upper and lower adjacent values(i.e., ±1.5 IQ); outside values have been omitted from the figure. CIsfor TK-216/rituximab in TMD8, TK-216/rituximab in Karpas422,TK-216/rituximab in OCI-LY-10 are not plotted due to CI values >3.Combinations tested included bendamustine, bortezomib, ibrutinib,idelalisib, lenalidomide, OTX015 (birabresib, CAS No. 202590-98-5),PQR309 (bimiralisib, CAS No. 1225037-39-7 (free base)), selinexor,venetoclax, and vincristine. Synergism was observed for TK216 incombination with bortezomib (TMD8), idelalisib (OCI-LY-10, KARPAS422),lenalidomide (OCI-LY-10, TMD8), OTX015 (KARPAS422), venetoclax(OCI-LY-10, KARPAS422, TMD8), and vincristine (SU-DHL-4). An additiveeffect was observed for TK216 in combination with bendamustine(KARPAS422), ibrutinib (OCI-LY-10, TMD8), lidelalisib (TMD8), OTX015(OCI-LY-10, TMD8), PQR309 (KARPAS422, SU-DHL-4, TMD8), selinexor(KARPAS422, TMD8), and vincristine (OCI-LY-10, KARPAS422). No benefiteffects was observed for TK216 in combination with bendamustine(OCI-LY-10, SU-DHL-4, TMD8), bortezomib (OCI-LY-10), idelalisib(SU-DHL-4), OTX015 (SU-DHL-4), PQR309 (OCI-LY-10), selinexor (OCI-LY-10,SU-DHL-4), venetoclax (SU-DHL-4), and vincristine (TMD8).

DETAILED DESCRIPTION

The following description and examples illustrate a preferred embodimentof the present invention in detail. Those of skill in the art willrecognize that there are numerous variations and modifications of thisinvention that are encompassed by its scope. Accordingly, thedescription of a preferred embodiment should not be deemed to limit thescope of the present invention

Chromosomal translocations generating oncogenic transcription factorsare the hallmark of a variety of tumors, including many sarcomas. Ewingsarcoma family of tumors (ESFTs) are characterized by thet(11;22)(q24;q12) translocation that generates the Ewing sarcomabreakpoint region 1 and Friend leukemia virus integration 1 (EWS-FLI1)fusion transcription factor responsible for the highly malignantphenotype of this tumor. Continued expression of EWS-FLI1 is believed tobe critical for ESFT cell survival. EWS-FLI1 is an attractive treatmenttarget for Ewing sarcoma because of its malignant cell specificity.Furthermore, experimental evidence indicates that EWS/FLI expression isessential for Ewing sarcoma tumor cells. In vitro targeting of EWS-FLI1with antisense oligodeoxynucleotides and RNA interference (RNAi)inhibits Ewing sarcoma cell viability, growth, and oncogenictransformation, supporting EWS-FLI1 attenuation as a potential treatmentmodality. The therapeutic agents of the preferred embodiments have broadapplicability to a larger group of tumors, and are useful astherapeutics for treatment for other oncogenic transcription factorrelated malignancies such as chemotherapy-resistant sarcomas andleukemias and difficult to treat tumors such as Ewing's sarcoma.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety unless stated otherwise. In the event that there is a pluralityof definitions for a term herein, those in this section prevail unlessstated otherwise.

As used herein, any “R” group(s) such as, without limitation, R₁, R₂,R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and R₁₂ represent substituentsthat can be attached to the indicated atom. An R group may besubstituted or unsubstituted. If two “R” groups are described as being“taken together” the R groups and the atoms they are attached to canform a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle. Forexample, without limitation, if R^(a) and R^(b) of an NR^(a)R^(b) groupare indicated to be “taken together,” it means that they are covalentlybonded to one another to form a ring:

In addition, if two “R” groups are described as being “taken together”with the atom(s) to which they are attached to form a ring as analternative, the R groups may not be limited to the variables orsubstituents defined previously.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that comprises a fully saturated (no double or triple bonds)hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms(whenever it appears herein, a numerical range such as “1 to 20” refersto each integer in the given range; e.g., “1 to 20 carbon atoms” meansthat the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 20 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 10 carbon atoms. The alkyl group could also be alower alkyl having 1 to 6 carbon atoms. The alkyl group of the compoundsmay be designated as “C₁-C₆ alkyl” or similar designations. By way ofexample only, “C₁-C₆ alkyl” indicates that there are one to six carbonatoms in the alkyl chain, i.e., the alkyl chain is selected from methyl,ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl,pentyl (straight and branched) and hexyl (straight and branched).Typical alkyl groups include, but are in no way limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl(straight and branched) and hexyl (straight and branched). The alkylgroup may be substituted or unsubstituted.

As used herein, “cycloalkyl” refers to a completely saturated (no doubleor triple bonds) mono- or multi-cyclic hydrocarbon ring system. Whencomposed of two or more rings, the rings may be joined together in afused fashion. Cycloalkyl groups can contain 3 to 10 atoms in thering(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may beunsubstituted or substituted. Typical cycloalkyl groups include, but arein no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

As used herein, “aryl” refers to a carbocyclic (all carbon) mono-cyclicor multi-cyclic aromatic ring system (including fused ring systems wheretwo carbocyclic rings share a chemical bond) that has a fullydelocalized pi-electron system throughout all the rings. The number ofcarbon atoms in an aryl group can vary. For example, the aryl group canbe a C₆-C₁₄ aryl group, a C₆-C₁₀ aryl group, or a C₆ aryl group.Examples of aryl groups include, but are not limited to, benzene,naphthalene and azulene. An aryl group may be substituted orunsubstituted.

As used herein, “heteroaryl” refers to a mono-cyclic or multi-cyclicaromatic ring system (a ring system with fully delocalized pi-electronsystem) that contain(s) one or more heteroatoms (for example, 1 to 5heteroatoms), that is, an element other than carbon, including but notlimited to, nitrogen, oxygen and sulfur. The number of atoms in thering(s) of a heteroaryl group can vary. For example, the heteroarylgroup can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in thering(s) or 5 to 6 atoms in the ring(s). Furthermore, the term“heteroaryl” includes fused ring systems where two rings, such as atleast one aryl ring and at least one heteroaryl ring, or at least twoheteroaryl rings, share at least one chemical bond. Examples ofheteroaryl rings include, but are not limited to, furan, furazan,thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole,1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole,1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole,indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole,isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline,isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. Aheteroaryl group may be substituted or unsubstituted.

As used herein, heterocycloalkyl refers to three-, four-, five-, six-,seven-, eight-, nine-, ten-, up to 18-membered mono-cyclic, bicyclic,and tricyclic ring system wherein carbon atoms together with from 1 to 5heteroatoms constitute said ring system. A heterocycle may optionallycontain one or more unsaturated bonds situated in such a way, however,that a fully delocalized pi-electron system does not occur throughoutall the rings. The heteroatom(s) is an element other than carbonincluding, but not limited to, oxygen, sulfur, and nitrogen. Aheterocycle may further contain one or more carbonyl or thiocarbonylfunctionalities, so as to make the definition include oxo-systems andthio-systems such as lactams, lactones, cyclic imides, cyclic thioimidesand cyclic carbamates. When composed of two or more rings, the rings maybe joined together in a fused fashion. Additionally, any nitrogens in aheterocycloalky may be quaternized. Heterocycloalkyl groups may beunsubstituted or substituted. Examples of such heterocycloalkyl groupsinclude but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane,1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane,1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane,1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide,succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine,hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine,imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline,oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine,oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine,pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine,2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran,thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, andtheir benzo-fused analogs (e.g., benzimidazolidinone,tetrahydroquinoline and 3,4-methylenedioxyphenyl).

The term “pharmaceutically acceptable salt” refers to a salt of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, the salt is an acidaddition salt of the compound. Pharmaceutical salts can be obtained byreacting a compound with inorganic acids such as hydrohalic acid (e.g.,hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid andphosphoric acid. Pharmaceutical salts can also be obtained by reacting acompound with an organic acid such as aliphatic or aromatic carboxylicor sulfonic acids, for example formic, acetic, succinic, lactic, malic,tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic,p-toluensulfonic, salicylic or naphthalenesulfonic acid. Pharmaceuticalsalts can also be obtained by reacting a compound with a base to form asalt such as an ammonium salt, an alkali metal salt, such as a sodium ora potassium salt, an alkaline earth metal salt, such as a calcium or amagnesium salt, a salt of organic bases such as dicyclohexylamine,N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C₁-C₇ alkylamine,cyclohexylamine, triethanolamine, ethylenediamine, and salts with aminoacids such as arginine and lysine.

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, enantiomerically enriched, racemicmixture, diastereomerically pure, diastereomerically enriched, or astereoisomeric mixture. In addition it is understood that, in anycompound described herein having one or more double bond(s) generatinggeometrical isomers that can be defined as E or Z, each double bond mayindependently be E or Z a mixture thereof.

It is to be understood that where compounds disclosed herein haveunfilled valencies, then the valencies are to be filled with hydrogensor isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2(deuterium).

It is understood that the compounds described herein can be labeledisotopically. Substitution with isotopes such as deuterium may affordcertain therapeutic advantages resulting from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements. Each chemical element as represented in a compoundstructure may include any isotope of said element. For example, in acompound structure a hydrogen atom may be explicitly disclosed orunderstood to be present in the compound. At any position of thecompound that a hydrogen atom may be present, the hydrogen atom can beany isotope of hydrogen, including but not limited to hydrogen-1(protium) and hydrogen-2 (deuterium). Thus, reference herein to acompound encompasses all potential isotopic forms unless the contextclearly dictates otherwise.

It is understood that the methods and combinations described hereininclude crystalline forms (also known as polymorphs, which include thedifferent crystal packing arrangements of the same elemental compositionof a compound), amorphous phases, salts, solvates, and hydrates. In someembodiments, the compounds described herein exist in solvated forms withpharmaceutically acceptable solvents such as water, ethanol, or thelike. In other embodiments, the compounds described herein exist inunsolvated form. Solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and may be formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, or the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Where a range of values is provided, it is understood that the upper andlower limit, and each intervening value between the upper and lowerlimit of the range is encompassed within the embodiments.

Methods of Treatment

In a first aspect, a method for inducing aptosis in a cell comprising amyeloblast produced in acute myeloid leukemia or a lymphocyte producedin diffuse large B cell lymphoma, comprising contacting the cell with aneffective amount of a combination of venetoclax and a compound having astructure of Formula (I):

-   -   or a stereoisomer, a pharmaceutically acceptable salt, or        solvate thereof, wherein R₁, R₂, R₃, and R₄ are independently        selected from the group consisting of H, Cl, —CN and —CF₃;        wherein A is selected from the group consisting of H and C₁₋₆        alkyl; wherein D is selected from the group consisting of —OH        and —O(C₁₋₆ alkyl); wherein R₅ and R₆ are independently selected        from the group consisting of H, F, and C₁₋₆ alkyl, or wherein R₅        and R₆ taken together form a substituted or unsubstituted        cycloalkyl ring; wherein R₁₂ is independently selected from the        group consisting of C₃₋₈ cycloalkyl and

wherein R₇, R₈, R₉, R₁₀ and R₁₁ are independently selected from thegroup consisting of H, halogen, CN, CF₃, C₁₋₆ alkyl, aryl, heteroaryl,—O(C₁₋₆ alkyl), —O(aryl), —O(heteroaryl), —CO₂H, —CO₂(C₁₋₆ alkyl),—NHSO₂(C₁₋₆ alkyl), —NHSO₂(aryl), —NHCONH(C₁₋₆ alkyl), —NHCON(C₁₋₆alkyl)₂, —N(C₁₋₆ alkyl)CONH₂, —N(C₁₋₆ alkyl)CONH(C₁₋₆ alkyl), —N(C₁₋₆alkyl)CON(C₁₋₆ alkyl)₂, —SO₂(C₁₋₆ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, C₃₋₈ cycloalkyl, and C₃₋₈ heterocycloalkyl.

In an embodiment of the first aspect, R₉ is selected from the groupconsisting of H, halogen, CN, CF₃, C₁₋₆ alkyl, aryl, heteroaryl,—O(aryl), —O(heteroaryl), —CO₂H, —CO₂(C₁₋₆ alkyl), —NHSO₂(C₁₋₆ alkyl),—NHSO₂(aryl), —NHCONH(C₁₋₆ alkyl), —NHCON(C₁₋₆ alkyl)₂, —N(C₁₋₆alkyl)CONH₂, —N(C₁₋₆ alkyl)CONH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)CON(C₁₋₆alkyl)₂, —SO₂(C₁₋₆ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₆ alkyl), —SO₂N(C₁₋₆alkyl)₂, C₃₋₈ cycloalkyl, and C₃₋₈ heterocycloalkyl.

In an embodiment of the first aspect, the cell is mammalian.

In an embodiment of the first aspect, the cell is human.

In an embodiment of the first aspect, the cell is in vitro.

In an embodiment of the first aspect, the cell is in vivo.

In a second aspect, a method of treating acute myeloid leukemia ordiffuse large B cell lymphoma is provided, comprising administering to apatient in need thereof an anti-proliferative amount of a combination ofvenetoclax and a compound having a structure of Formula (I):

-   -   or a stereoisomer, a pharmaceutically acceptable salt, or        solvate thereof, wherein R₁, R₂, R₃, and R₄ are independently        selected from the group consisting of H, Cl, —CN and —CF₃;        wherein A is selected from the group consisting of H and C₁₋₆        alkyl; wherein D is selected from the group consisting of —OH        and —O(C₁₋₆ alkyl); wherein R₅ and R₆ are independently selected        from the group consisting of H, F, and C₁₋₆ alkyl, or wherein R₅        and R₆ taken together form a substituted or unsubstituted        cycloalkyl ring; wherein R₁₂ is independently selected from the        group consisting of C₃₋₈ cycloalkyl and

wherein R₇, R₈, R₉, R₁₀ and R₁₁ are independently selected from thegroup consisting of H, halogen, CN, CF₃, C₁₋₆ alkyl, aryl, heteroaryl,—O(C₁₋₆ alkyl), —O(aryl), —O(heteroaryl), —CO₂H, —CO₂(C₁₋₆ alkyl),—NHSO₂(C₁₋₆ alkyl), —NHSO₂(aryl), —NHCONH(C₁₋₆ alkyl), —NHCON(C₁₋₆alkyl)₂, —N(C₁₋₆ alkyl)CONH₂, —N(C₁₋₆ alkyl)CONH(C₁₋₆ alkyl), —N(C₁₋₆alkyl)CON(C₁₋₆ alkyl)₂, —SO₂(C₁₋₆ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, C₃₋₈ cycloalkyl, and C₃₋₈ heterocycloalkyl.

In an embodiment of the second aspect, R₉ is selected from the groupconsisting of H, halogen, CN, CF₃, C₁₋₆ alkyl, aryl, heteroaryl,—O(aryl), —O(heteroaryl), —CO₂H, —CO₂(C₁₋₆ alkyl), —NHSO₂(C₁₋₆ alkyl),—NHSO₂(aryl), —NHCONH(C₁₋₆ alkyl), —NHCON(C₁₋₆ alkyl)₂, —N(C₁₋₆alkyl)CONH₂, —N(C₁₋₆ alkyl)CONH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)CON(C₁₋₆alkyl)₂, —SO₂(C₁₋₆ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₆ alkyl), —SO₂N(C₁₋₆alkyl)₂, C₃₋₈ cycloalkyl, and C₃₋₈ heterocycloalkyl.

In a third aspect, use is provided of a combination of venetoclax and acompound having a structure of Formula (I):

-   -   or a stereoisomer, a pharmaceutically acceptable salt, or        solvate thereof, for the treatment of acute myeloid leukemia or        diffuse large B cell lymphoma, wherein R₁, R₂, R₃, and R₄ are        independently selected from the group consisting of H, Cl, —CN        and —CF₃; wherein A is selected from the group consisting of H        and C₁₋₆ alkyl; wherein D is selected from the group consisting        of —OH and —O(C₁₋₆ alkyl); wherein R₅ and R₆ are independently        selected from the group consisting of H, F, and C₁₋₆ alkyl, or        wherein R₅ and R₆ taken together form a substituted or        unsubstituted cycloalkyl ring; wherein R₁₂ is independently        selected from the group consisting of substituted or        unsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈        heterocycloalkyl,

wherein R₇, R₈, R₉, R₁₀ and R₁₁ are independently selected from thegroup consisting of H, halogen, CN, CF₃, C₁₋₆ alkyl, aryl, heteroaryl,—O(C₁₋₆ alkyl), —O(aryl), —O(heteroaryl), —CO₂H, —CO₂(C₁₋₆ alkyl),—NHSO₂(C₁₋₆ alkyl), —NHSO₂(aryl), —NHCONH(C₁₋₆ alkyl), —NHCON(C₁₋₆alkyl)₂, —N(C₁₋₆ alkyl)CONH₂, —N(C₁₋₆ alkyl)CONH(C₁₋₆ alkyl), —N(C₁₋₆alkyl)CON(C₁₋₆ alkyl)₂, —SO₂(C₁₋₆ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, C₃₋₈ cycloalkyl, and C₃₋₈ heterocycloalkyl; andwherein R¹³ selected from the group consisting of —O(C₁₋₆ alkyl) and—N(C₁₋₆ alkyl)₂.

In an embodiment of the third aspect, R₉ is selected from the groupconsisting of H, halogen, CN, CF₃, C₁₋₆ alkyl, aryl, heteroaryl,—O(aryl), —O(heteroaryl), —CO₂H, —CO₂(C₁₋₆ alkyl), —NHSO₂(C₁₋₆ alkyl),—NHSO₂(aryl), —NHCONH(C₁₋₆ alkyl), —NHCON(C₁₋₆ alkyl)₂, —N(C₁₋₆alkyl)CONH₂, —N(C₁₋₆ alkyl)CONH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)CON(C₁₋₆alkyl)₂, —SO₂(C₁₋₆ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₆ alkyl), —SO₂N(C₁₋₆alkyl)₂, C₃₋₈ cycloalkyl, and C₃₋₈ heterocycloalkyl.

In an embodiment of the first aspect, R₁₂ is unsubstituted, orsubstituted by a halogen, e.g., Cl or F.

In an embodiment of the first aspect, the second aspect, or the thirdaspect, R₉ is selected from the group consisting of aziridinyl,azetidinyl, pyrrolidinyl, and morpholinolyl.

In an embodiment of the first aspect, the second aspect, or the thirdaspect, R₉ is selected from the group consisting of isopropyl andcyclopropyl.

In an embodiment of the first aspect, the second aspect, or the thirdaspect, the compound has a structure of Formula (Ia):

-   -   or a stereoisomer, a pharmaceutically acceptable salt, or        solvate thereof, wherein R₁, R₂, R₃, and R₄ are independently        selected from the group consisting of H and Cl; wherein R₇, R₈,        R₁₀ and R₁₁ are independently selected from the group consisting        of H and halogen; and wherein R₉ is independently selected from        the group consisting C₃₋₈ cycloalkyl and C₃₋₈ heterocycloalkyl.

In an embodiment of the first aspect, the second aspect, or the thirdaspect, R₁ and R₄ are Cl and R₂ and R₃ are H.

In an embodiment of the first aspect, the second aspect, or the thirdaspect, the compound has a structure selected from the group consistingof:

-   -   or a stereoisomer, a pharmaceutically acceptable salt, ester, or        solvate thereof.

In an embodiment of the first aspect, the second aspect, or the thirdaspect, the compound is selected from the group consisting of:

-   -   or a stereoisomer, a pharmaceutically acceptable salt, ester, or        solvate thereof.

The method of any one of claims 1-6, wherein the compound has astructure selected from the group consisting of:

or a stereoisomer, a pharmaceutically acceptable salt, ester, or solvatethereof.

In an embodiment of the first aspect, the second aspect, or the thirdaspect, the compound has a structure selected from the group consistingof:

or a stereoisomer, a pharmaceutically acceptable salt, ester, or solvatethereof.

In an embodiment of the first aspect, the second aspect, or the thirdaspect, the compound has a structure:

-   -   or a stereoisomer, a pharmaceutically acceptable salt, ester, or        solvate thereof.

In an embodiment of the first aspect, the second aspect, or the thirdaspect, the compound has a structure:

-   -   or a stereoisomer, a pharmaceutically acceptable salt, ester, or        solvate thereof.

In an embodiment of the first aspect, the second aspect, or the thirdaspect, the compound has a structure:

-   -   or a stereoisomer, a pharmaceutically acceptable salt, ester, or        solvate thereof.

Synthetic Methods

Compounds of Formula (I) described herein may be prepared in variousways. General synthetic routes to compounds of Formula (I) are shown anddescribed herein. The routes shown and described herein are illustrativeonly and are not intended, nor are they to be construed, to limit thescope of the claims in any manner whatsoever. Those skilled in the artwill be able to recognize modifications of the disclosed syntheses andto devise alternate routes based on the disclosures herein; all suchmodifications and alternate routes are within the scope of the claims.

Depending upon the substituents present, the small molecule inhibitorscan be in a form of a pharmaceutically acceptable salt. The terms“pharmaceutically acceptable salt” as used herein are broad terms, andis to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to salts preparedfrom pharmaceutically acceptable, non-toxic acids or bases. Suitablepharmaceutically acceptable salts include metallic salts, e.g., salts ofaluminum, zinc, alkali metal salts such as lithium, sodium, andpotassium salts, alkaline earth metal salts such as calcium andmagnesium salts; organic salts, e.g., salts of lysine,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine), procaine, and tris;salts of free acids and bases; inorganic salts, e.g., sulfate,hydrochloride, and hydrobromide; and other salts which are currently inwidespread pharmaceutical use and are listed in sources well known tothose of skill in the art, such as, for example, The Merck Index. Anysuitable constituent can be selected to make a salt of the therapeuticagents discussed herein, provided that it is non-toxic and does notsubstantially interfere with the desired activity.

The compounds of preferred embodiments can include isomers, racemates,optical isomers, enantiomers, diastereomers, tautomers, and cis/transconformers. All such isomeric forms are included within preferredembodiments, including mixtures thereof. As discussed above, thecompounds of preferred embodiments may have chiral centers, for example,they may contain asymmetric carbon atoms and may thus exist in the formof enantiomers or diastereoisomers and mixtures thereof, e.g.,racemates. Asymmetric carbon atom(s) can be present in the (R)- or(S)-configuration, or can be present as mixtures of the (R)- and(S)-forms. The following are isomeric forms of the compounds of Formula(I):

The compounds can be in amorphous form, or in crystalline forms. Thecrystalline forms of the compounds of preferred embodiments can exist aspolymorphs, which are included in preferred embodiments. In addition,some of the compounds of preferred embodiments may also form solvateswith water or other organic solvents. Such solvates are similarlyincluded within the scope of the preferred embodiments.

Certain Pharmaceutical Compositions

It is generally preferred to administer the inhibitors of preferredembodiments in an intravenous or subcutaneous unit dosage form; however,other routes of administration are also contemplated. Contemplatedroutes of administration include but are not limited to oral,parenteral, intravenous, and subcutaneous. The inhibitors of preferredembodiments can be formulated into liquid preparations for, e.g., oraladministration. Suitable forms include suspensions, syrups, elixirs, andthe like. Particularly preferred unit dosage forms for oraladministration include tablets and capsules. Unit dosage formsconfigured for administration once a day are particularly preferred;however, in certain embodiments it can be desirable to configure theunit dosage form for administration twice a day, or more.

The pharmaceutical compositions of preferred embodiments are preferablyisotonic with the blood or other body fluid of the recipient. Theisotonicity of the compositions can be attained using sodium tartrate,propylene glycol or other inorganic or organic solutes. Sodium chlorideis particularly preferred. Buffering agents can be employed, such asacetic acid and salts, citric acid and salts, boric acid and salts, andphosphoric acid and salts. Parenteral vehicles include sodium chloridesolution, Ringer's dextrose, dextrose and sodium chloride, lactatedRinger's or fixed oils. Intravenous vehicles include fluid and nutrientreplenishers, electrolyte replenishers (such as those based on Ringer'sdextrose), and the like.

Viscosity of the pharmaceutical compositions can be maintained at theselected level using a pharmaceutically acceptable thickening agent.Methylcellulose is preferred because it is readily and economicallyavailable and is easy to work with. Other suitable thickening agentsinclude, for example, xanthan gum, carboxymethyl cellulose,hydroxypropyl cellulose, carbomer, and the like. The preferredconcentration of the thickener will depend upon the thickening agentselected. An amount is preferably used that will achieve the selectedviscosity. Viscous compositions are normally prepared from solutions bythe addition of such thickening agents.

A pharmaceutically acceptable preservative can be employed to increasethe shelf life of the pharmaceutical compositions. Benzyl alcohol can besuitable, although a variety of preservatives including, for example,parabens, thimerosal, chlorobutanol, or benzalkonium chloride can alsobe employed. A suitable concentration of the preservative is typicallyfrom about 0.02% to about 2% based on the total weight of thecomposition, although larger or smaller amounts can be desirabledepending upon the agent selected. Reducing agents, as described above,can be advantageously used to maintain good shelf life of theformulation.

The inhibitors of preferred embodiments can be in admixture with asuitable carrier, diluent, or excipient such as sterile water,physiological saline, glucose, or the like, and can contain auxiliarysubstances such as wetting or emulsifying agents, pH buffering agents,gelling or viscosity enhancing additives, preservatives, flavoringagents, colors, and the like, depending upon the route of administrationand the preparation desired. See, e.g., “Remington: The Science andPractice of Pharmacy”, Lippincott Williams & Wilkins; 20th edition (June1, 2003) and “Remington's Pharmaceutical Sciences,” Mack Pub. Co.;18^(th) and 19^(th) editions (December 1985, and June 1990,respectively). Such preparations can include complexing agents, metalions, polymeric compounds such as polyacetic acid, polyglycolic acid,hydrogels, dextran, and the like, liposomes, microemulsions, micelles,unilamellar or multilamellar vesicles, erythrocyte ghosts orspheroblasts. Suitable lipids for liposomal formulation include, withoutlimitation, monoglycerides, diglycerides, sulfatides, lysolecithin,phospholipids, saponin, bile acids, and the like. The presence of suchadditional components can influence the physical state, solubility,stability, rate of in vivo release, and rate of in vivo clearance, andare thus chosen according to the intended application, such that thecharacteristics of the carrier are tailored to the selected route ofadministration.

For oral administration, the pharmaceutical compositions can be providedas a tablet, aqueous or oil suspension, dispersible powder or granule,emulsion, hard or soft capsule, syrup or elixir. Compositions intendedfor oral use can be prepared according to any method known in the artfor the manufacture of pharmaceutical compositions and can include oneor more of the following agents: sweeteners, flavoring agents, coloringagents and preservatives. Aqueous suspensions can contain the activeingredient in admixture with excipients suitable for the manufacture ofaqueous suspensions.

Formulations for oral use can also be provided as hard gelatin capsules,wherein the active ingredient(s) are mixed with an inert solid diluent,such as calcium carbonate, calcium phosphate, or kaolin, or as softgelatin capsules. In soft capsules, the inhibitors can be dissolved orsuspended in suitable liquids, such as water or an oil medium, such aspeanut oil, olive oil, fatty oils, liquid paraffin, or liquidpolyethylene glycols. Stabilizers and microspheres formulated for oraladministration can also be used. Capsules can include push-fit capsulesmade of gelatin, as well as soft, sealed capsules made of gelatin and aplasticizer, such as glycerol or sorbitol. The push-fit capsules cancontain the active ingredient in admixture with fillers such as lactose,binders such as starches, and/or lubricants such as talc or magnesiumstearate and, optionally, stabilizers.

Tablets can be uncoated or coated by known methods to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period of time. For example, atime delay material such as glyceryl monostearate can be used. Whenadministered in solid form, such as tablet form, the solid formtypically comprises from about 0.001 wt. % or less to about 50 wt. % ormore of active ingredient(s), preferably from about 0.005, 0.01, 0.02,0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6,0.7, 0.8, 0.9, or 1 wt. % to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20,25, 30, 35, 40, or 45 wt. %.

Tablets can contain the active ingredients in admixture with non-toxicpharmaceutically acceptable excipients including inert materials. Forexample, a tablet can be prepared by compression or molding, optionally,with one or more additional ingredients. Compressed tablets can beprepared by compressing in a suitable machine the active ingredients ina free-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets can be made by molding, in a suitable machine, a mixtureof the powdered inhibitor moistened with an inert liquid diluent.

Preferably, each tablet or capsule contains from about 1 mg or less toabout 1,000 mg or more of an inhibitor of the preferred embodiments,more preferably from about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 mgto about 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700,750, 800, or 900 mg. Most preferably, tablets or capsules are providedin a range of dosages to permit divided dosages to be administered. Adosage appropriate to the patient and the number of doses to beadministered daily can thus be conveniently selected. In certainembodiments it can be preferred to incorporate two or more of thetherapeutic agents to be administered into a single tablet or otherdosage form (e.g., in a combination therapy); however, in otherembodiments it can be preferred to provide the therapeutic agents inseparate dosage forms.

Suitable inert materials include diluents, such as carbohydrates,mannitol, lactose, anhydrous lactose, cellulose, sucrose, modifieddextrans, starch, and the like, or inorganic salts such as calciumtriphosphate, calcium phosphate, sodium phosphate, calcium carbonate,sodium carbonate, magnesium carbonate, and sodium chloride.Disintegrants or granulating agents can be included in the formulation,for example, starches such as corn starch, alginic acid, sodium starchglycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin,sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose,natural sponge and bentonite, insoluble cationic exchange resins,powdered gums such as agar, karaya or tragacanth, or alginic acid orsalts thereof.

Binders can be used to form a hard tablet. Binders include materialsfrom natural products such as acacia, tragacanth, starch and gelatin,methyl cellulose, ethyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, and the like.

Lubricants, such as stearic acid or magnesium or calcium salts thereof,polytetrafluoroethylene, liquid paraffin, vegetable oils and waxes,sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol,starch, talc, pyrogenic silica, hydrated silicoaluminate, and the like,can be included in tablet formulations.

Surfactants can also be employed, for example, anionic detergents suchas sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctylsodium sulfonate, cationic such as benzalkonium chloride or benzethoniumchloride, or nonionic detergents such as polyoxyethylene hydrogenatedcastor oil, glycerol monostearate, polysorbates, sucrose fatty acidester, methyl cellulose, or carboxymethyl cellulose.

Controlled release formulations can be employed wherein the amifostineor analog(s) thereof is incorporated into an inert matrix that permitsrelease by either diffusion or leaching mechanisms. Slowly degeneratingmatrices can also be incorporated into the formulation. Other deliverysystems can include timed release, delayed release, or sustained releasedelivery systems.

Coatings can be used, for example, nonenteric materials such as methylcellulose, ethyl cellulose, hydroxy ethyl cellulose, methylhydroxy-ethylcellulose, hydroxypropyl cellulose, hydroxypropyl-methyl cellulose,sodium carboxy-methyl cellulose, providone and the polyethylene glycols,or enteric materials such as phthalic acid esters. Dyestuffs or pigmentscan be added for identification or to characterize differentcombinations of inhibitor doses

When administered orally in liquid form, a liquid carrier such as water,petroleum, oils of animal or plant origin such as peanut oil, mineraloil, soybean oil, or sesame oil, or synthetic oils can be added to theactive ingredient(s). Physiological saline solution, dextrose, or othersaccharide solution, or glycols such as ethylene glycol, propyleneglycol, or polyethylene glycol are also suitable liquid carriers. Thepharmaceutical compositions can also be in the form of oil-in-wateremulsions. The oily phase can be a vegetable oil, such as olive orarachis oil, a mineral oil such as liquid paraffin, or a mixturethereof. Suitable emulsifying agents include naturally-occurring gumssuch as gum acacia and gum tragacanth, naturally occurring phosphatides,such as soybean lecithin, esters or partial esters derived from fattyacids and hexitol anhydrides, such as sorbitan mono-oleate, andcondensation products of these partial esters with ethylene oxide, suchas polyoxyethylene sorbitan mono-oleate. The emulsions can also containsweetening and flavoring agents.

Pulmonary delivery can also be employed. The compound is delivered tothe lungs while inhaling and traverses across the lung epithelial liningto the blood stream. A wide range of mechanical devices designed forpulmonary delivery of therapeutic products can be employed, includingbut not limited to nebulizers, metered dose inhalers, and powderinhalers, all of which are familiar to those skilled in the art. Thesedevices employ formulations suitable for the dispensing of compound.Typically, each formulation is specific to the type of device employedand can involve the use of an appropriate propellant material, inaddition to diluents, adjuvants, and/or carriers useful in therapy.

The compound and/or other optional active ingredients are advantageouslyprepared for pulmonary delivery in particulate form with an averageparticle size of from 0.1 μm or less to 10 μm or more, more preferablyfrom about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 μm to about 1.0,1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0,8.5, 9.0, or 9.5 μm. Pharmaceutically acceptable carriers for pulmonarydelivery of inhibitor include carbohydrates such as trehalose, mannitol,xylitol, sucrose, lactose, and sorbitol. Other ingredients for use informulations can include DPPC, DOPE, DSPC, and DOPC. Natural orsynthetic surfactants can be used, including polyethylene glycol anddextrans, such as cyclodextran. Bile salts and other related enhancers,as well as cellulose and cellulose derivatives, and amino acids can alsobe used. Liposomes, microcapsules, microspheres, inclusion complexes,and other types of carriers can also be employed.

Pharmaceutical formulations suitable for use with a nebulizer, eitherjet or ultrasonic, typically comprise the inhibitor dissolved orsuspended in water at a concentration of about 0.01 or less to 100 mg ormore of inhibitor per mL of solution, preferably from about 0.1, 1, 2,3, 4, 5, 6, 7, 8, 9, or 10 mg to about 15, 20, 25, 30, 35, 40, 45, 50,55, 60, 65, 70, 75, 80, 85, or 90 mg per mL of solution. The formulationcan also include a buffer and a simple sugar (e.g., for proteinstabilization and regulation of osmotic pressure). The nebulizerformulation can also contain a surfactant, to reduce or prevent surfaceinduced aggregation of the inhibitor caused by atomization of thesolution in forming the aerosol.

Formulations for use with a metered-dose inhaler device generallycomprise a finely divided powder containing the active ingredientssuspended in a propellant with the aid of a surfactant. The propellantcan include conventional propellants, such as chlorofluorocarbons,hydrochlorofluorocarbons, hydrofluorocarbons, and hydrocarbons.Preferred propellants include trichlorofluoromethane,dichlorodifluoromethane, dichlorotetrafluoroethanol,1,1,1,2-tetrafluoroethane, and combinations thereof. Suitablesurfactants include sorbitan trioleate, soya lecithin, and oleic acid.

Formulations for dispensing from a powder inhaler device typicallycomprise a finely divided dry powder containing inhibitor, optionallyincluding a bulking agent, such as lactose, sorbitol, sucrose, mannitol,trehalose, or xylitol in an amount that facilitates dispersal of thepowder from the device, typically from about 1 wt. % or less to 99 wt. %or more of the formulation, preferably from about 5, 10, 15, 20, 25, 30,35, 40, 45, or 50 wt. % to about 55, 60, 65, 70, 75, 80, 85, or 90 wt. %of the formulation.

When a compound of the preferred embodiments is administered byintravenous, parenteral, or other injection, it is preferably in theform of a pyrogen-free, parenterally acceptable aqueous solution oroleaginous suspension. Suspensions can be formulated according tomethods well known in the art using suitable dispersing or wettingagents and suspending agents. The preparation of acceptable aqueoussolutions with suitable pH, isotonicity, stability, and the like, iswithin the skill in the art. A preferred pharmaceutical composition forinjection preferably contains an isotonic vehicle such as1,3-butanediol, water, isotonic sodium chloride solution, Ringer'ssolution, dextrose solution, dextrose and sodium chloride solution,lactated Ringer's solution, or other vehicles as are known in the art.In addition, sterile fixed oils can be employed conventionally as asolvent or suspending medium. For this purpose, any bland fixed oil canbe employed including synthetic mono or diglycerides. In addition, fattyacids such as oleic acid can likewise be used in the formation ofinjectable preparations. The pharmaceutical compositions can alsocontain stabilizers, preservatives, buffers, antioxidants, or otheradditives known to those of skill in the art.

The duration of the injection can be adjusted depending upon variousfactors, and can comprise a single injection administered over thecourse of a few seconds or less, to 0.5, 0.1, 0.25, 0.5, 0.75, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, or 24 hours or more of continuous intravenous administration.

The compounds of the preferred embodiments can additionally employadjunct components conventionally found in pharmaceutical compositionsin their art-established fashion and at their art-established levels.Thus, for example, the compositions can contain additional compatiblepharmaceutically active materials for combination therapy (such assupplementary antimicrobials, antipruritics, astringents, localanesthetics, anti-inflammatory agents, reducing agents,chemotherapeutics and the like), or can contain materials useful inphysically formulating various dosage forms of the preferredembodiments, such as excipients, dyes, thickening agents, stabilizers,preservatives or antioxidants. Anti-cancer agents that can be used incombination with the compounds of preferred embodiments include, but arenot limited to, vinca alkaloids such as vinblastine and vincristine;anthracyclines such as doxorubicin, daunorubicin, epirubicin;anthracenes such as bisantrene and mitoxantrone; epipodophyllo-toxinssuch as etoposide and teniposide; and other anticancer drugs such asactinomyocin D, mithomycin C, mitramycin, methotrexate, docetaxel,etoposide (VP-16), paclitaxel, docetaxel, and adriamycin); andimmunosuppressants (e.g., cyclosporine A, tacrolimus). In someembodiments, the compounds, compositions and methods provided herein maybe in combination with histone deacetylase inhibitors (HDAC), aurorakinase inhibitors, demethylating agents (such as 5-AZA cytidine),immunotherapy with natural killer cells, IGF-IR antibodies, Ewingantigen antibodies, immunosuppressive drugs, and hydroxyurea. Examplesof histone deacetylase inhibitors include vorinostat, romidepsin,panobinostat, valproic acid, belinostat, mocetinostat, givinostat, andtrichostatin A. Examples of aurora kinase inhibitors include ZM447439,hesperadin, and VX-680. Examples of demethylating agents include5-azacytidine, 5-azadeoxycytidine, and procaine. Examples ofimmunosuppressive drugs include 6-mercaptopurine, and azathioprine.

Certain Kits

The compounds of the preferred embodiments can be provided to anadministering physician or other health care professional in the form ofa kit. The kit is a package which houses a container which contains thecompounds in a suitable pharmaceutical composition, and instructions foradministering the pharmaceutical composition to a subject. The kit canoptionally also contain one or more additional therapeutic agents, e.g.,chemotherapeutics currently employed for treating the sarcomas describedherein. For example, a kit containing one or more compositionscomprising compounds of the preferred embodiments in combination withone or more additional chemotherapeutic agents can be provided, orseparate pharmaceutical compositions containing an inhibitor of thepreferred embodiments and additional therapeutic agents can be provided.The kit can also contain separate doses of a compound of the preferredembodiments for serial or sequential administration. The kit canoptionally contain one or more diagnostic tools and instructions foruse. The kit can contain suitable delivery devices, e.g., syringes, andthe like, along with instructions for administering the inhibitor(s) andany other therapeutic agent. The kit can optionally contain instructionsfor storage, reconstitution (if applicable), and administration of anyor all therapeutic agents included. The kits can include a plurality ofcontainers reflecting the number of administrations to be given to asubject.

EXAMPLES

The ETS family of transcription factors is critical for development,differentiation, proliferation, and plays an important role in apoptosisand tissue remodeling. Transcriptional consequences of ETS proteinderegulation by overexpression, gene fusion, and modulation by RAS/MAPKand PI3K signaling are linked to alterations in normal cell functions,and lead to increased proliferation, sustained angiogenesis, invasion,and metastasis. Overexpressed ETS proteins and ETS family fusionproteins have been reported in acute myeloid leukemia (AML) and diffuselarge B cell lymphoma (DLBCL). In DLBCL, the 11q24.3 region has beenidentified as a recurrent lesion and a contributor to the pathogenesisof disease, leading to the deregulation of ETS family members, ETS1 andFLI1. Additionally, in AML, the overexpression and translocations ofERG, an ETS family member, has been shown to be associated with poorprognosis in complex or normal karyotypes.

TK216 is a first in class, small molecule that directly binds EWS-FLI1inhibiting the biological activity of ETS-family transcription factoroncoproteins and is currently under clinical investigation in patientswith Ewing sarcoma. The EWS1-FLI1 is a fusion protein that has beenshown to be the driver of Ewing Sarcoma (ES). In preclinical potencymodels, TK216 blocked the binding between EWS-FLI1 and RNA helicase A,showed a significant transcriptional decrease in COS7 cells transfectedwith a EWS-FLI1 responsive promoter (EC₅₀<100 nM), and inhibited theproliferation of A4573 cells (EWS-FLI1 expressing Ewing sarcoma cellline) at nanomolar concentrations (EC₅₀<200 nM).

4,7-Dichloro-3-(2-(4-cyclopropylphenyl)-2-oxoethyl)-3-hydroxyindolin-2-one

TK216 also had anti-proliferative effects, causes cell cycle arrest, andinduces apoptosis in a panel of AML and DLBCL cell lines withderegulated ETS family members. Upregulation of FLI1 and/or ERG ETSfamily members was observed in the myeloid cell lines evaluated (HL-60,Kasumi-1, ML-2, MOLM-13, MOLM-16, and THP-1). Treatment with TK216showed a decrease in cellular viability and induced dose-dependentapoptosis of cells at 48 hours. Similarly, in a panel of DLBCL celllines (TMD-8, HBL-1, U2932, DOHH2, WSU-DLCL2, OCI-Ly18, and OCI-Ly19),TK216 treatment resulted in a decrease in cellular proliferation and anincrease in apoptosis. In vivo efficacy studies in xenograft models ofDLBCL indicated anti-tumor activity consistent with in vitro findings,confirming the utility and efficacy of TK216 in the treatment of AML andDLBCL by targeting the aberrant expression and translocations in theETS-family of transcription factors, which contribute to thepathogenesis of the disease.

The mechanism of action of TK216 is illustrated in FIG. 1. Asillustrated in FIG. 1, TK216 is active in oncogenesis(anchorage-independent growth; tumors in mice), altered gene expression(↑ E2G2 (chromatin regulator; ↑ VEGF-A (angiogenesis)), and alternativesplicing (cyclin D1b (activates cell cycle); ARID1A-ex18L (chromatinregulator). TK216 inhibited aptosis (programmed cell death; inhibitstumor growth), altered gene expression (↓ E2G2; ↓ VEGF-A), and variantisoforms (cyclin D1a (slows cell cycle); ARID1A-ex185 (non-oncogenic)).

TK216 treatment inhibited EWS-FLI1 protein interactions, leading to adecrease in transcription and proliferation. FLI1 was immunoprecipitatedfollowing treatment with TK216 or DMSO control in A4573 (see FIG. 2).

TK216 reduced transcriptional activity in COS7 cells co-transfected withEWS-FLI1 and NROB1 reporter-luciferase plasmids which contain EWS-FLI1DNA-binding sites, as shown in FIG. 3.

Treatment with TK216 resulted in a dose-dependent inhibition ofproliferation in Ewing Sarcoma A4573 cell line, as shown in FIG. 4.

TK216 displayed anti-proliferative activity in AML cell lines. The IC₅₀of TK216 for each cell line was determined in a 72 hr CellTiter-Gloassay, as shown in FIG. 5 and TABLE 1.

TABLE 1 TK216 IC₅₀ in AML Cell Lines TK216-2 Cisplatin Cell line IC₅₀(μM) IC₅₀ (μM) HL-60 0.363 1.931 Kasumi-1 0.393 4.560 ML-2 0.291 1.395MOLM-13 0.228 0.798 MOLM-16 0.129 2.190 THP-1 0.152 1.359

TK216 displayed anti-proliferative activity in DLBCL cell lines. TheIC₅₀ of TK216 for each cell line was determined in a 72 hr CellTiter-Gloassay, as shown in FIG. 6 and TABLE 2.

TABLE 2 TK216 IC₅₀ in DLBCL Cell Lines TK216 Cell line IC₅₀ (μM) TMD-80.152 HBL-1 0.304 DOHH2 0.160 U2932 0.127 WSU-DLCL2 0.897 OCI-Ly18 0.095OCI-Ly19 0.106

TK216 induced apoptosis in DLBCL cell lines. Cells were treated withvarious concentrations of TK216 for 18 h and apoptosis was assessed bydetection of cleaved-Caspase 3. The amount of cleaved-Caspase 3 wasnormalized to b-actin and presented as fold over control, as shown inFIG. 7 and FIG. 8.

TK216 displayed synergy when combined with BCL-2 (ABT199) and BTK(ACP196) inhibitors. The median-effect analysis was used to determinesynergism, antagonism, or additivity of TK216 when combined with ABT199(BCL-2i) and ACP196 (BTKi). CalcuSyn software was used to determine theCombination Index (CI) using the Chou/Talalay equation, as shown in FIG.9 and FIG. 10.

TK216 displayed anti-tumor activity in a DLBCL xenograft model. Theanti-tumor activity of TK216 was assessed in nude mice harboring TMD-8tumors, a DLBCL-ABC xenograft model. TK216 was administered orally as asolution at 100 mg/kg BID for 13 days. Results are shown in FIG. 11.

Treatment with TK216 resulted in tumor growth inhibition. TK216 resultedin 77% tumor growth inhibition of the TMD-8 xenograft model whencompared to vehicle control following 13 days of treatment, as shown inFIG. 12.

As the above data demonstrated, TK216 is a first in class, smallmolecule that directly binds EWS-FLI1 inhibiting the biological activityof ETS-family transcription factor. In AML and DLBCL cell lines withderegulated ETS-family members, treatment with TK216 resulted in potentinhibition of proliferation and the induction of apoptosis. Combinationof TK216 with BCL-2 and BTK inhibitors in DLBCL cell lines lead tosynergistic activity and allowed for a more effective inhibition of cellproliferation. Daily, oral administration of TK216 potently inhibitedtumor growth in xenograft models of DLBCL with deregulated expression ofETS-family members, and is well-tolerated. The inhibition of theEWS-FLI1 oncogene offers a promising approach for the treatment of EwingSarcoma, e.g., relapsed/refractory Ewing Sarcoma.

Venetoclax (4-(4-{[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl }-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide)is used for the treatment of chronic lymphocytic leukemia, e.g., inpatients who have relapsed or have been refractory to previous treatmentand who have the 17p deletion genetic mutation.

Venetoclax

TK216 was tested in combination with venetoclax and has beendemonstrated to exhibit synergism in dose-effect in DLBCL cell lines. Ineach of FIGS. 13-15, the top curve (×) was for the combination therapy,the middle curve (⊚) was for TK216, and the bottom curve (+) was forvenetoclax. FIG. 13 is a dose-effect curve for TK216 in combination withvenetoclax in the TMD8 cell line. FIG. 14 is a dose-effect curve forTK216 in combination with venetoclax in the U2932 cell line. FIG. 15 isa dose-effect curve for TK216 in combination with venetoclax in the HLB1cell line.

Dose-effect testing was conducted in DLBLC cell lines (TMD8, HBL1,U2932) indicating a synergistic effect across doses, as shown in FIG.16.

ETS transcription factors, such as FLI1 and SPIB, are recurrentlyderegulated in human lymphomas. The small molecule YK-4-279 (alsoreferred to as YK-279 or YK279, is4,7-dichloro-3-hydroxy-3-(2-(4-methoxyphenyl)-2-oxoethyl)indolin-2-one)inhibits binding of EWS1-FLI1 fusion protein to RHA with growth arrestand apoptosis in Ewing sarcoma cells, and exhibits in vitroanti-lymphoma activity.

YK-4-279

TK-216 is a YK-4-279 clinical derivative that is in phase 1 for patientswith relapsed or refractory Ewing sarcoma. Preclinical testing has beenconducted for TK-216 in lymphoma models.

56 lymphoma cell lines [27 diffuse large B cell lymphoma (DLBCL); 10mantle cell lymphoma; 6 marginal zone lymphoma; 5 anaplastic largeT-cell lymphoma; 8 others] were exposed to TK-216 increasing doses for72 h using a Tecan D300e Digital Dispenser and 384 well plates. Cellproliferation was measured with MTT. In vivo study was done in NOD-SCIDmice; treatments were started with approximately sc 60 mm3 tumorvolumes. The study demonstrated TK-216 was very active, with a medianIC50 of 449 nM (95% C.I.: 367-506), as shown in FIG. 1. Sensitivity wasnot affected by the lymphoma cell of origin (B vs T; activated B celltype DLBCL versus germinal center type DLBCL) or MYC and TP53 status.There was a non-statistically significant trend for lower sensitivity incell lines bearing BCL2 chromosomal translocation (P=0.07, DLBCL only;P=0.06, all cell lines). The anti-tumor activity was mainly cytotoxic,as confirmed performing cell cycle analysis and Annexin V staining in 6DLBCL cell lines (TMD8, U2932, HBL1, OCI-LY-18, WSU-DLCL2, DOHH2; TK-216or DMSO for 24, 48, 72 h), in which a time-dependent apoptosis waspreceded by a G2/M arrest, as shown in FIG. 2.

Antitumor activity was then tested using DLBCL TMD8 cells xenografts, asshown in FIG. 3. Compared with a control group (n=10), mice treated withTK-216 (100 mg/Kg, BID; n=9) clearly presented a reduction in tumorgrowth, already evident at day 3 and becoming much stronger with time(D3, D5, D8, D11: P<0.01; D13, P not available since control group hadto be stopped due to tumor volume) and a four-times reduction in tumorvolume at D11 (P<0.01). TK-216 was also tested in combination with othertargeted agents in DLBCL cell lines, as shown in FIG. 4. A benefit wasobserved with the combination of TK-216 with the immunomodulatorlenalidomide (synergism in 2/2 activated B cell type DLBCL), with thebromodomain and extra-terminal protein (BET) inhibitor OTX015 (MK-8628)(synergism in 2/4 cells and additive effect in 1/4 cells), with theanti-CD20 monoclonal antibody rituximab (synergism in 2/3 cells) andwith the BCL2 inhibitor venetoclax (synergism in 3/4 cells). The lattersynergism could be linked to the previously mentioned negative trendbetween TK-216 IC50 values and the presence of BCL2 translocation.

The test results demonstrated that TK-216 presented strong preclinicalanti-lymphoma activity, both as a single agent and in combination withother therapeutic agents.

The two main DLBCL subtypes are the germinal center B cell (GCB) and theABC types, characterized by individual biologic and clinical features.Since up to 40% DLBCL patients are still not cured with the standardtreatments, there is the need for novel therapies. YK-4-279 is a smallmolecule that inhibits binding of the EWS1-FLI1 fusion protein to RHA,resulting in growth arrest and apoptosis in Ewing sarcoma cells. Itsderivative, TK-216, is the first in class inhibitor of the ETS-family oftranscription factors in phase I (NCT02657005 for relapsed or refractoryEwing sarcoma). Both compounds have shown promising preclinicalanti-lymphoma activity. Data has been obtained on their mechanism ofaction in DLBCL.

Cell lines were exposed to YK-4-279 or TK-216, alone or in combinationwith other compounds, for 72 h using a Tecan D300e Digital Dispenser and96 well plates. Cell proliferation was measured with MTT. Synergy wasdetermined with the Chou-Talalay combination index. Gene expressionprofiling (GEP) was performed with the Illumina HumanHT 12 ExpressionBeadChips. In vivo studies were done in NOD-SCID mice and treatmentsstarted with 60 mm3 tumor volumes sc.

TK-216 showed strong in vitro and in vivo anti-lymphoma activity.Anti-tumor activity has been demonstrated for YK-4-279 in the same ABCDLBCL model (TMD8 xenograft) as for TK-216. Compared with a controlgroup (n=10), mice treated with YK-4-279 (100 mg/Kg, BID; n=9) clearlypresented a reduction in tumor growth at D8 and D11 (P<0.01) and D13 (Pnot available since the control group had to be stopped due to tumorvolume). In accordance with combination data showing a specificsynergism of TK-216 when combined with the immunomodulatory drug (IMID)lenalidomide in ABC DLBCL, when YK-4-279 was combined with theBTK-inhibitor ibrutinib, the PI3K-delta inhibitor idelalisib, the BETinhibitor OTX-015 and lenalidomide in four DLBCL cell lines (2 ABC, 2GCB), the biggest benefit was achieved with the combination of YK-4-279plus lenalidomide with synergism in both ABC DLBCL. Since lenalidomideis active in mantle cell lymphoma (MCL), the synergism of thecombination of TK-216 and lenalidomide was confirmed also in two MCLcell lines.

With the aim to understand the mechanism of action of YK-4-279 andTK-216, the baseline RNA expression levels of the different ETS factorswere correlated with sensitivity to the drugs. SPIB was the genepresenting the most significant negative correlation with both YK-4-279and TK-216, especially among the ABC DLBCL cell lines (P<0.05). SPIB isa known oncogene for ABC DLBCL (Lenz et al, PNAS 2008) and is involvedin the response to lenalidomide in ABC DLBCL (Yang et al, Cancer Cell2012). YK-4-279 inhibits the binding of EWS1-FLI1 to the helicases RHAand DDX5 (Selvanathan et al, PNAS 2012). Thus, it was assessed whetherYK-4-279 and TK-216 can have a similar effect on SPIB and whether theyinduce cellular effects similar to lenalidomide. Protein modellingdemonstrated that the 3D structure of FLI1 and SPIB are highlyoverlapping. Co-IP experiments showed the binding of SPIB to RHA andDDX5 in two ABC DLBCL cell lines. The binding to RHA and, to a lesserextent, to DDX5 was decreased upon exposing the cells to TK216 orYK-4-279 (500 nM, 4-10 h). Similarly to lenalidomide (Yang et al, CancerCell 2012), TK-216 decreased IRF4 and upregulated IRF7 protein in cells.GEP of two ABC DLBCL cell lines exposed to the active (S)-enantiomer orto the inactive (R)-enantiomer (500 nM, 4-8 h) showed that (S)-YK-4-279caused an important upregulation of multiple snoRNAs—an effectcompatible with an interference of the compound on helicases and RNAediting. In ABC DLBCL, the ETS inhibitor YK-4-279 and its clinicalderivative TK-216 interfere with SPIB and helicases involved in RNAediting. Moreover, both compounds act similarly to lenalidomideinhibiting IRF4 and upregulating IRF7 and synergize with the IMID inboth ABC DLBCL and MCL.

Exemplary Methods and Compositions

Method 1: A method for inducing aptosis in a cell comprising amyeloblast produced in acute myeloid leukemia or a lymphocyte producedin diffuse large B cell lymphoma, comprising contacting the cell with aneffective amount of a combination of:

-   -   at least one therapeutic agent selected from the group        consisting of an immunomodulator, a bromodomain, an        extra-terminal protein inhibitor, an anti-CD20 monoclonal        antibody, and a BCL2 inhibitor; and    -   a compound having a structure of Formula (I):

-   -   or a stereoisomer, a pharmaceutically acceptable salt, or        solvate thereof, wherein R₁, R₂, R₃, and R₄ are independently        selected from the group consisting of H, Cl, —CN and —CF₃;        wherein A is selected from the group consisting of H and C₁₋₆        alkyl; wherein D is selected from the group consisting of —OH        and —O(C₁₋₆ alkyl); wherein R₅ and R₆ are independently selected        from the group consisting of H, F, and C₁₋₆ alkyl, or wherein R₅        and R₆ taken together form a substituted or unsubstituted        cycloalkyl ring; wherein R₁₂ is independently selected from the        group consisting of substituted or unsubstituted C₃₋₈        cycloalkyl, substituted or unsubstituted C₃₋₈ heterocycloalkyl,

wherein R₇, R₈, R₉, R₁₀ and R₁₁ are independently selected from thegroup consisting of H, halogen, CN, CF₃, C₁₋₆ alkyl, aryl, heteroaryl,—O(C₁₋₆ alkyl), —O(aryl), —O(heteroaryl), —CO₂H, —CO₂(C₁₋₆ alkyl),—NHSO₂(C₁₋₆ alkyl), —NHSO₂(aryl), —NHCONH(C₁₋₆ alkyl), —NHCON(C₁₋₆alkyl)₂, —N(C₁₋₆ alkyl)CONH₂, —N(C₁₋₆ alkyl)CONH(C₁₋₆ alkyl), —N(C₁₋₆alkyl)CON(C₁₋₆ alkyl)₂, —SO₂(C₁₋₆ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂; and wherein R¹³ selected from the group consistingof —O(C₁₋₆ alkyl) and —N(C₁₋₆ alkyl)₂.

Method 2: A method of treating acute myeloid leukemia or diffuse large Bcell lymphoma, comprising administering to a patient in need thereof ananti-proliferative amount of a combination of:

-   -   at least one therapeutic agent selected from the group        consisting of an immunomodulator, a bromodomain, an        extra-terminal protein inhibitor, an anti-CD20 monoclonal        antibody, and a BCL2 inhibitor; and    -   a compound having a structure of Formula (I):

-   -   or a stereoisomer, a pharmaceutically acceptable salt, or        solvate thereof, wherein R₁, R₂, R₃, and R₄ are independently        selected from the group consisting of H, Cl, —CN and —CF₃;        wherein A is selected from the group consisting of H and C₁₋₆        alkyl; wherein D is selected from the group consisting of —OH        and —O(C₁₋₆ alkyl); wherein R₅ and R₆ are independently selected        from the group consisting of H, F, and C₁₋₆ alkyl, or wherein R₅        and R₆ taken together form a substituted or unsubstituted        cycloalkyl ring; wherein R₁₂ is independently selected from the        group consisting of substituted or unsubstituted C₃₋₈        cycloalkyl, substituted or unsubstituted C₃₋₈ heterocycloalkyl,

wherein R₇, R₈, R₉, R₁₀ and R₁₁ are independently selected from thegroup consisting of H, halogen, CN, CF₃, C₁₋₆ alkyl, aryl, heteroaryl,—O(C₁₋₆ alkyl), —O(aryl), —O(heteroaryl), —CO₂H, —CO₂(C₁₋₆ alkyl),—NHSO₂(C₁₋₆ alkyl), —NHSO₂(aryl), —NHCONH(C₁₋₆ alkyl), —NHCON(C₁₋₆alkyl)₂, —N(C₁₋₆ alkyl)CONH₂, —N(C₁₋₆ alkyl)CONH(C₁₋₆ alkyl), —N(C₁₋₆alkyl)CON(C₁₋₆ alkyl)₂, —SO₂(C₁₋₆ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂; and wherein R¹³ selected from the group consistingof —O(C₁₋₆ alkyl) and —N(C₁₋₆ alkyl)₂.

Method 3: The method of any one of Methods 1 through 2, wherein R₉ isselected from the group consisting of H, halogen, CN, CF₃, C₁₋₆ alkyl,aryl, heteroaryl, —O(aryl), —O(heteroaryl), —CO₂H, —CO₂(C₁₋₆ alkyl),—NHSO₂(C₁₋₆ alkyl), —NHSO₂(aryl), —NHCONH(C₁₋₆ alkyl), —NHCON(C₁₋₆alkyl)₂, —N(C₁₋₆ alkyl)CONH₂, —N(C₁₋₆ alkyl)CONH(C₁₋₆ alkyl), —N(C₁₋₆alkyl)CON(C₁₋₆ alkyl)₂, —SO₂(C₁₋₆ alkyl), -SO₂NH₂, —SO₂NH(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂; and wherein R¹³ selected from the group consistingof —O(C₁₋₆ alkyl) and —N(C₁₋₆ alkyl)₂.

Method 4: The method of any one of Methods 1 through 3, wherein the cellis mammalian.

Method 5: The method of any one of Methods 1 through 4, wherein the cellis human.

Method 6: The method of any one of Methods 1 through 5, wherein the cellis in vitro.

Method 7: The method of any one of Methods 1 through 6, wherein the cellis in vivo.

Method 8: The method of any one of Methods 1 through 7, wherein thetherapeutic agent is an immunomodulator.

Method 9: The method of any one of Methods 1 through 7, wherein theimmunomodulator is lenalidomide.

Method 10: The method of any one of Methods 1 through 7, wherein thetherapeutic agent is a bromodomain and extra-terminal protein inhibitor.

Method 11: The method of any one of Methods 1 through 7, wherein thebromodomain and extra-terminal protein inhibitor is OTX015.

Method 12: The method of any one of Methods 1 through 7, wherein thetherapeutic agent is an anti-CD20 monoclonal antibody

Method 13: The method of any one of Methods 1 through 7, wherein theanti-CD20 monoclonal antibody is rituximab.

Method 14: The method of any one of Methods 1 through 7, wherein thetherapeutic agent is a BCL2 inhibitor.

Method 15: The method of any one of Methods 1 through 7, wherein theBCL2 inhibitor is venetoclax.

Method 16: The method of any one of Methods 1 through 15, wherein R₉ isselected from the group consisting of aziridinyl, azetidinyl,pyrrolidinyl, and morpholinolyl.

Method 17: The method of any one of Methods 1 through 15, wherein R₉ isselected from the group consisting of isopropyl and cyclopropyl.

Method 18: The method of any one of Methods 1 through 15, wherein thecompound has a structure of Formula (Ia):

-   -   or a stereoisomer, a pharmaceutically acceptable salt, or        solvate thereof, wherein R₁, R₂, R₃, and R₄ are independently        selected from the group consisting of H and Cl; wherein R₇, R₈,        R₁₀ and R₁₁ are independently selected from the group consisting        of H and halogen; and wherein R₉ is independently selected from        the group consisting C₃₋₈ cycloalkyl and C₃₋₈ heterocycloalkyl.

Method 19: The method of any one of Methods 1 through 15, wherein R₁ andR₄ are Cl and R₂ and R₃ are H.

Method 20: The method of any one of Methods 1 through 15, wherein thecompound has a structure selected from the group consisting of:

-   -   or a stereoisomer, a pharmaceutically acceptable salt, ester, or        solvate thereof.

Method 21: The method of any one of Methods 1 through 15, wherein thecompound has a structure selected from the group consisting of:

-   -   or a stereoisomer, a pharmaceutically acceptable salt, ester, or        solvate thereof.

Method 22: The method of any one of Methods 1 through 15, wherein thecompound has a structure selected from the group consisting of:

-   -   or a stereoisomer, a pharmaceutically acceptable salt, ester, or        solvate thereof.

Method 23: The method of any one of Methods 1 through 15, wherein thecompound has a structure selected from the group consisting of:

-   -   or a stereoisomer, a pharmaceutically acceptable salt, ester, or        solvate thereof.

Method 24: The method of any one of Methods 1 through 15, wherein thecompound has a structure:

-   -   or a stereoisomer, a pharmaceutically acceptable salt, ester, or        solvate thereof.

Method 25: The method of any one of Methods 1 through 15, wherein thecompound has a structure:

-   -   or a stereoisomer, a pharmaceutically acceptable salt, ester, or        solvate thereof.

Method 26: The method of any one of Methods 1 through 15, wherein thecompound has a structure:

-   -   or a stereoisomer, a pharmaceutically acceptable salt, ester, or        solvate thereof.

Composition 27: A pharmaceutical composition, comprising:

-   -   at least one therapeutic agent selected from the group        consisting of an immunomodulator, a bromodomain, an        extra-terminal protein inhibitor, an anti-CD20 monoclonal        antibody, and a BCL2 inhibitor; and    -   a compound having a structure of Formula (I):

-   -   or a stereoisomer, a pharmaceutically acceptable salt, or        solvate thereof, wherein R₁, R₂, R₃, and R₄ are independently        selected from the group consisting of H, Cl, —CN and —CF₃;        wherein A is selected from the group consisting of H and C₁₋₆        alkyl; wherein D is selected from the group consisting of —OH        and —O(C₁₋₆ alkyl); wherein R₅ and R₆ are independently selected        from the group consisting of H, F, and C₁₋₆ alkyl, or wherein R₅        and R₆ taken together form a substituted or unsubstituted        cycloalkyl ring; wherein R₁₂ is independently selected from the        group consisting of substituted or unsubstituted C₃₋₈        cycloalkyl, substituted or unsubstituted C₃₋₈ heterocycloalkyl,

wherein R₇, R₈, R₉, R₁₀ and R₁₁ are independently selected from thegroup consisting of H, halogen, CN, CF₃, C₁₋₆ alkyl, aryl, heteroaryl,—O(C₁₋₆ alkyl), —O(aryl), —O(heteroaryl), —CO₂H, —CO₂(C₁₋₆ alkyl),—NHSO₂(C₁₋₆ alkyl), —NHSO₂(aryl), —NHCONH(C₁₋₆ alkyl), —NHCON(C₁₋₆alkyl)₂, —N(C₁₋₆ alkyl)CONH₂, —N(C₁₋₆ alkyl)CONH(C₁₋₆ alkyl), —N(C₁₋₆alkyl)CON(C₁₋₆ alkyl)₂, —SO₂(C₁₋₆ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂; and wherein R¹³ selected from the group consistingof —O(C₁₋₆ alkyl) and —N(C₁₋₆ alkyl)₂.

Composition 28: The composition of Composition 1, wherein R₉ is selectedfrom the group consisting of H, halogen, CN, CF₃, C₁₋₆ alkyl, aryl,heteroaryl, —O(aryl), —O(heteroaryl), —CO₂H, —CO₂(C₁₋₆ alkyl),—NHSO₂(C₁₋₆ alkyl), —NHSO₂(aryl), —NHCONH(C₁₋₆ alkyl), —NHCON(C₁₋₆alkyl)₂, —N(C₁₋₆ alkyl)CONH₂, —N(C₁₋₆ alkyl)CONH(C₁₋₆ alkyl), —N(C₁₋₆alkyl)CON(C₁₋₆ alkyl)₂, —SO₂(C₁₋₆ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂; and wherein R¹³ selected from the group consistingof —O(C₁₋₆ alkyl) and —N(C₁₋₆ alkyl)₂.

Composition 29: The composition of any one of Compositions 27 through28, wherein the therapeutic agent is an immunomodulator.

Composition 30: The composition of any one of Compositions 27 through28, wherein the immunomodulator is lenalidomide.

Composition 31: The composition of any one of Compositions 27 through28, wherein the therapeutic agent is a bromodomain and extra-terminalprotein inhibitor.

Composition 32: The composition of any one of Compositions 27 through28, wherein the bromodomain and extra-terminal protein inhibitor isOTX015.

Composition 33: The composition of any one of Compositions 27 through28, wherein the therapeutic agent is an anti-CD20 monoclonal antibody

Composition 34: The composition of any one of Compositions 27 through28, wherein the anti-CD20 monoclonal antibody is rituximab.

Composition 35: The composition of any one of Compositions 27 through28, wherein the therapeutic agent is a BCL2 inhibitor.

Composition 36: The composition of any one of Compositions 27 through28, wherein the BCL2 inhibitor is venetoclax.

Composition 37: The composition of any one of Compositions 27 through37, wherein R₉ is selected from the group consisting of aziridinyl,azetidinyl, pyrrolidinyl, and morpholinolyl.

Composition 38: The composition of any one of Compositions 27 through37, wherein R₉ is selected from the group consisting of isopropyl andcyclopropyl.

Composition 39: The composition of any one of Compositions 27 through37, wherein the compound has a structure of Formula (Ia):

-   -   or a stereoisomer, a pharmaceutically acceptable salt, or        solvate thereof, wherein R₁, R₂, R₃, and R₄ are independently        selected from the group consisting of H and Cl; wherein R₇, R₈,        R₁₀ and R₁₁ are independently selected from the group consisting        of H and halogen; and wherein R₉ is independently selected from        the group consisting C₃₋₈ cycloalkyl and C₃₋₈ heterocycloalkyl.

Composition 40: The composition of any one of Compositions 27 through37, wherein R₁ and R₄ are Cl and R₂ and R₃ are H.

Composition 41: The composition of any one of Compositions 27 through37, wherein the compound has a structure selected from the groupconsisting of:

-   -   or a stereoisomer, a pharmaceutically acceptable salt, ester, or        solvate thereof.

Composition 42: The composition of any one of Compositions 27 through37, wherein the compound has a structure selected from the groupconsisting of:

-   -   or a stereoisomer, a pharmaceutically acceptable salt, ester, or        solvate thereof.

Composition 43: The composition of any one of Compositions 27 through37, wherein the compound has a structure selected from the groupconsisting of:

-   -   or a stereoisomer, a pharmaceutically acceptable salt, ester, or        solvate thereof.

Composition 44: The composition of any one of Compositions 27 through37, wherein the compound has a structure selected from the groupconsisting of:

-   -   or a stereoisomer, a pharmaceutically acceptable salt, ester, or        solvate thereof.

Composition 45: The composition of any one of Compositions 27 through37, wherein the compound has a structure:

-   -   or a stereoisomer, a pharmaceutically acceptable salt, ester, or        solvate thereof.

Composition 46: The composition of any one of Compositions 27 through37, wherein the compound has a structure:

-   -   or a stereoisomer, a pharmaceutically acceptable salt, ester, or        solvate thereof.

Composition 47, wherein the compound has a structure:

-   -   or a stereoisomer, a pharmaceutically acceptable salt, ester, or        solvate thereof.

While the disclosure has been illustrated and described in detail in thedrawings and foregoing description, such illustration and descriptionare to be considered illustrative or exemplary and not restrictive. Thedisclosure is not limited to the disclosed embodiments. Variations tothe disclosed embodiments can be understood and effected by thoseskilled in the art in practicing the claimed disclosure, from a study ofthe drawings, the disclosure and the appended claims.

All references cited herein are incorporated herein by reference intheir entirety. To the extent publications and patents or patentapplications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

Unless otherwise defined, all terms (including technical and scientificterms) are to be given their ordinary and customary meaning to a personof ordinary skill in the art, and are not to be limited to a special orcustomized meaning unless expressly so defined herein. It should benoted that the use of particular terminology when describing certainfeatures or aspects of the disclosure should not be taken to imply thatthe terminology is being re-defined herein to be restricted to includeany specific characteristics of the features or aspects of thedisclosure with which that terminology is associated.

Where a range of values is provided, it is understood that the upper andlower limit, and each intervening value between the upper and lowerlimit of the range is encompassed within the embodiments.

Terms and phrases used in this application, and variations thereof,especially in the appended claims, unless otherwise expressly stated,should be construed as open ended as opposed to limiting. As examples ofthe foregoing, the term ‘including’ should be read to mean ‘including,without limitation,’ including but not limited to,' or the like; theterm ‘comprising’ as used herein is synonymous with ‘including,’‘containing,’ or ‘characterized by,’ and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps; theterm ‘having’ should be interpreted as ‘having at least;’ the term‘includes’ should be interpreted as ‘includes but is not limited to;’the term ‘example’ is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof; adjectives suchas ‘known’, ‘normal’, ‘standard’, and terms of similar meaning shouldnot be construed as limiting the item described to a given time periodor to an item available as of a given time, but instead should be readto encompass known, normal, or standard technologies that may beavailable or known now or at any time in the future; and use of termslike ‘preferably,’ preferred,‘desired,’ or ‘desirable,’ and words ofsimilar meaning should not be understood as implying that certainfeatures are critical, essential, or even important to the structure orfunction of the invention, but instead as merely intended to highlightalternative or additional features that may or may not be utilized in aparticular embodiment of the invention. Likewise, a group of itemslinked with the conjunction ‘and’ should not be read as requiring thateach and every one of those items be present in the grouping, but rathershould be read as ‘and/or’ unless expressly stated otherwise. Similarly,a group of items linked with the conjunction ‘or’ should not be read asrequiring mutual exclusivity among that group, but rather should be readas ‘and/or’ unless expressly stated otherwise.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity. The indefinite article “a” or “an” does not exclude aplurality. The mere fact that certain measures are recited in mutuallydifferent dependent claims does not indicate that a combination of thesemeasures cannot be used to advantage. Any reference signs in the claimsshould not be construed as limiting the scope.

It will be further understood by those within the art that if a specificnumber of an introduced claim recitation is intended, such an intentwill be explicitly recited in the claim, and in the absence of suchrecitation no such intent is present. For example, as an aid tounderstanding, the following appended claims may contain usage of theintroductory phrases “at least one” and “one or more” to introduce claimrecitations. However, the use of such phrases should not be construed toimply that the introduction of a claim recitation by the indefinitearticles “a” or “an” limits any particular claim containing suchintroduced claim recitation to embodiments containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should typically be interpreted to mean “atleast one” or “one or more”); the same holds true for the use ofdefinite articles used to introduce claim recitations. In addition, evenif a specific number of an introduced claim recitation is explicitlyrecited, those skilled in the art will recognize that such recitationshould typically be interpreted to mean at least the recited number(e.g., the bare recitation of “two recitations,” without othermodifiers, typically means at least two recitations, or two or morerecitations). Furthermore, in those instances where a conventionanalogous to “at least one of A, B, and C, etc.” is used, in generalsuch a construction is intended in the sense one having skill in the artwould understand the convention (e.g., “a system having at least one ofA, B, and C” would include but not be limited to systems that have Aalone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). In those instances where aconvention analogous to “at least one of A, B, or C, etc.” is used, ingeneral such a construction is intended in the sense one having skill inthe art would understand the convention (e.g., “a system having at leastone of A, B, or C” would include but not be limited to systems that haveA alone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). It will be furtherunderstood by those within the art that virtually any disjunctive wordand/or phrase presenting two or more alternative terms, whether in thedescription, claims, or drawings, should be understood to contemplatethe possibilities of including one of the terms, either of the terms, orboth terms. For example, the phrase “A or B” will be understood toinclude the possibilities of “A” or “B” or “A and B.”

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term ‘about.’ Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

Furthermore, although the foregoing has been described in some detail byway of illustrations and examples for purposes of clarity andunderstanding, it is apparent to those skilled in the art that certainchanges and modifications may be practiced. Therefore, the descriptionand examples should not be construed as limiting the scope of theinvention to the specific embodiments and examples described herein, butrather to also cover all modification and alternatives coming with thetrue scope and spirit of the invention.

What is claimed is:
 1. A method for inducing aptosis in a cellcomprising a myeloblast produced in acute myeloid leukemia or alymphocyte produced in diffuse large B cell lymphoma, comprisingcontacting the cell with an effective amount of a combination of: atleast one therapeutic agent selected from the group consisting of abromodomain, an extra-terminal protein inhibitor, an anti-CD20monoclonal antibody, and a BCL2 inhibitor; and a compound having astructure of Formula (I):

or a stereoisomer, a pharmaceutically acceptable salt, or solvatethereof, wherein R₁, R₂, R₃, and R₄ are independently selected from thegroup consisting of H, Cl, —CN and —CF₃; wherein A is selected from thegroup consisting of H and C₁₋₆ alkyl; wherein D is selected from thegroup consisting of —OH and —O(C₁₋₆ alkyl); wherein R₅ and R₆ areindependently selected from the group consisting of H, F, and C₁₋₆alkyl, or wherein R₅ and R₆ taken together form a substituted orunsubstituted cycloalkyl ring; wherein R₁₂ is independently selectedfrom the group consisting of substituted or unsubstituted C₃₋₈cycloalkyl, substituted or unsubstituted C₃₋₈ heterocycloalkyl,

wherein R₇, R₈, R₉, R₁₀ and R₁₁ are independently selected from thegroup consisting of H, halogen, CN, CF₃, C₁₋₆ alkyl, aryl, heteroaryl,—O(C₁₋₆ alkyl), —O(aryl), —O(heteroaryl), —CO₂H, —CO₂(C₁₋₆ alkyl),—NHSO₂(C₁₋₆ alkyl), —NHSO₂(aryl), —NHCONH(C₁₋₆ alkyl), —NHCON(C₁₋₆alkyl)₂, —N(C₁₋₆ alkyl)CONH₂, —N(C₁₋₆ alkyl)CONH(C₁₋₆ alkyl), —N(C₁₋₆alkyl)CON(C₁₋₆ alkyl)₂, —SO₂(C₁₋₆ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂; and wherein R¹³ selected from the group consistingof —O(C₁₋₆ alkyl) and —N(C₁₋₆ alkyl)₂.
 2. A method of treating acutemyeloid leukemia or diffuse large B cell lymphoma, comprisingadministering to a patient in need thereof an anti-proliferative amountof a combination of: at least one therapeutic agent selected from thegroup consisting of a bromodomain, an extra-terminal protein inhibitor,an anti-CD20 monoclonal antibody, and a BCL2 inhibitor; and a compoundhaving a structure of Formula (I):

or a stereoisomer, a pharmaceutically acceptable salt, or solvatethereof, wherein R₁, R₂, R₃, and R₄ are independently selected from thegroup consisting of H, Cl, —CN and —CF₃; wherein A is selected from thegroup consisting of H and C₁₋₆ alkyl; wherein D is selected from thegroup consisting of —OH and —O(C₁₋₆ alkyl); wherein R₅ and R₆ areindependently selected from the group consisting of H, F, and C₁₋₆alkyl, or wherein R₅ and R₆ taken together form a substituted orunsubstituted cycloalkyl ring; wherein R₁₂ is independently selectedfrom the group consisting of substituted or unsubstituted C₃₋₈cycloalkyl, substituted or unsubstituted C₃₋₈ heterocycloalkyl,

wherein R₇, R₈, R₉, R₁₀ and R₁₁ are independently selected from thegroup consisting of H, halogen, CN, CF₃, C₁₋₆ alkyl, aryl, heteroaryl,—O(C₁₋₆ alkyl), —O(aryl), —O(heteroaryl), —CO₂H, —CO₂(C₁₋₆ alkyl),—NHSO₂(C₁₋₆ alkyl), —NHSO₂(aryl), —NHCONH(C₁₋₆ alkyl), —NHCON(C₁₋₆alkyl)₂, —N(C₁₋₆ alkyl)CONH₂, —N(C₁₋₆ alkyl)CONH(C₁₋₆ alkyl), —N(C₁₋₆alkyl)CON(C₁₋₆ alkyl)₂, —SO₂(C₁₋₆ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂; and wherein R¹³ selected from the group consistingof —O(C₁₋₆ alkyl) and —N(C₁₋₆ alkyl)₂.
 3. The method of claim 1, whereinR₉ is selected from the group consisting of H, halogen, CN, CF₃, C₁₋₆alkyl, aryl, heteroaryl, —O(aryl), —O(heteroaryl), —CO₂H, —CO₂(C₁₋₆alkyl), —NHSO₂(C₁₋₆ alkyl), —NHSO₂(aryl), —NHCONH(C₁₋₆ alkyl),—NHCON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)CONH₂, —N(C₁₋₆ alkyl)CONH(C₁₋₆alkyl), —N(C₁₋₆ alkyl)CON(C₁₋₆ alkyl)₂, —SO₂(C₁₋₆ alkyl), —SO₂NH₂,—SO₂NH(C₁₋₆ alkyl), —SO₂N(C₁₋₆ alkyl)₂; and wherein R¹³ selected fromthe group consisting of —O(C₁₋₆ alkyl) and —N(C₁₋₆ alkyl)₂.
 4. Themethod of claim 1, wherein the therapeutic agent is a bromodomain. 5.The method of claim 1, wherein the immunomodulator is a BCL2 inhibitor.6. The method of claim 1, wherein the therapeutic agent is anextra-terminal protein inhibitor.
 7. The method of claim 6, wherein theextra-terminal protein inhibitor is OTX015.
 8. The method of claim 1,wherein the therapeutic agent is an anti-CD20 monoclonal antibody
 9. Themethod of claim 8, wherein the anti-CD20 monoclonal antibody isrituximab.
 10. The method of claim 1, wherein R₉ is selected from thegroup consisting of aziridinyl, azetidinyl, pyrrolidinyl, andmorpholinolyl.
 11. The method of claim 1, wherein R₉ is selected fromthe group consisting of isopropyl and cyclopropyl.
 12. The method ofclaim 1, wherein the compound has a structure of Formula (Ia):

or a stereoisomer, a pharmaceutically acceptable salt, or solvatethereof, wherein R₁, R₂, R₃, and R₄ are independently selected from thegroup consisting of H and Cl; wherein R₇, R₈, R₁₀ and R₁₁ areindependently selected from the group consisting of H and halogen; andwherein R₉ is independently selected from the group consisting C₃₋₈cycloalkyl and C₃₋₈ heterocycloalkyl.
 13. The method of claim 1, whereinR₁ and R₄ are Cl and R₂ and R₃ are H.
 14. The method of claim 1, whereinthe compound has a structure selected from the group consisting of:

or a stereoisomer, a pharmaceutically acceptable salt, ester, or solvatethereof.
 15. The method of claim 1, wherein the compound has a structureselected from the group consisting of:

or a stereoisomer, a pharmaceutically acceptable salt, ester, or solvatethereof.
 16. The method of claim 1, wherein the compound has a structureselected from the group consisting of:

or a stereoisomer, a pharmaceutically acceptable salt, ester, or solvatethereof.
 17. The method of claim 1, wherein the compound has astructure:

or a stereoisomer, a pharmaceutically acceptable salt, ester, or solvatethereof.
 18. A pharmaceutical composition, comprising: at least onetherapeutic agent selected from the group consisting of a bromodomain,an extra-terminal protein inhibitor, an anti-CD20 monoclonal antibody,and a BCL2 inhibitor; and a compound having a structure of Formula (I):

or a stereoisomer, a pharmaceutically acceptable salt, or solvatethereof, wherein R₁, R₂, R₃, and R₄ are independently selected from thegroup consisting of H, Cl, —CN and —CF₃; wherein A is selected from thegroup consisting of H and C₁₋₆ alkyl; wherein D is selected from thegroup consisting of —OH and —O(C₁₋₆ alkyl); wherein R₅ and R₆ areindependently selected from the group consisting of H, F, and C₁₋₆alkyl, or wherein R₅ and R₆ taken together form a substituted orunsubstituted cycloalkyl ring; wherein R₁₂ is independently selectedfrom the group consisting of substituted or unsubstituted C₃₋₈cycloalkyl, substituted or unsubstituted C₃₋₈ heterocycloalkyl,

wherein R₇, R₈, R₉, R₁₀ and R₁₁ are independently selected from thegroup consisting of H, halogen, CN, CF₃, C₁₋₆ alkyl, aryl, heteroaryl,—O(C₁₋₆ alkyl), —O(aryl), —O(heteroaryl), —CO₂H, —CO₂(C₁₋₆ alkyl),—NHSO₂(C₁₋₆ alkyl), —NHSO₂(aryl), —NHCONH(C₁₋₆ alkyl), —NHCON(C₁₋₆alkyl)₂, —N(C₁₋₆ alkyl)CONH₂, —N(C₁₋₆ alkyl)CONH(C₁₋₆ alkyl), —N(C₁₋₆alkyl)CON(C₁₋₆ alkyl)₂, —SO₂(C₁₋₆ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂; and wherein R¹³ selected from the group consistingof —O(C₁₋₆ alkyl) and —N(C₁₋₆ alkyl)₂.